Dihydrofuroindole compound or derivative thereof and use thereof

Abstract

The present invention provides a dihydrofuroindole compound having a structure as represented by formula I or a derivative thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritide thereof, and a use thereof. The dihydrofuroindole compound or the derivative thereof provided by the present invention is a compound having a novel structure. The compound has good inhibitory activity against both urate oxidase and a urate transporter, is an XOR / URAT1 dual inhibitor, has a good urate-lowering effect, good safety, good pharmacokinetic properties, and high druggability, can be used for preparing a urate-lowering medicament, and can be used for preventing and / or treating gout or hyperuricemia.

Description

Dihydrofuranoindole compounds or their derivatives and their applications

[0001] The present invention claims priority to Chinese patent application No. 2024101275857, filed with the Patent Office of China on January 30, 2024, entitled “Dihydrofuranoindole compounds or their derivatives and their applications,” the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of medicinal chemistry, and in particular to a class of dihydrofuranoindole compounds or derivatives thereof and applications thereof. Background Art

[0003] Uric acid is the final product of purine metabolism in humans and non-human primates, and is formed from xanthine by xanthine oxidase. Humans do not have uricase, so uric acid can only be excreted from the body through the intestines and kidneys. Due to the popularity of the Western diet, excessive purine intake through the diet, massive cell death in a short period of time (tumor lysis syndrome), and inefficient uric acid excretion pathways caused by genetic or environmental factors may all lead to hyperuricemia. A large amount of basic medical and clinical medical data shows that regardless of whether uric acid crystals are formed, high uric acid itself is an independent high-risk factor and is related to the pathogenesis of various diseases in the body (such as diabetic nephropathy, other chronic kidney diseases, and cardiovascular and cerebrovascular diseases). The normal range of uric acid in human blood is 3-6.0 mg / dL (180-360 μmol), and the solubility of uric acid is <6.5 mg / dL (37°C, pH 7.0). Exceeding this concentration can lead to crystallization, and lower pH and temperature promote crystallization. Crystallization can deposit in distal joints or other parts of the body (such as blood vessels and kidneys), causing cell damage and inflammation, causing great pain to patients and seriously affecting their quality of life. Hyperuricemia affects 8% of the general population, and gout patients account for 4% of the total population. Among people over 60 years old, over 10% will experience gout attacks.

[0004] Currently, the main drugs used to lower uric acid are as follows: allopurinol or febuxostat are used to inhibit xanthine oxidase, thereby reducing the production of uric acid; benzbromarone is used to interfere with the reabsorption of uric acid in the kidneys, thereby promoting the excretion of uric acid; or for patients with refractory hyperuricemia, exogenous recombinant or modified uricase (even in combination with immunosuppressants) is used to degrade uric acid; or some single-target drugs targeting uric acid transporters, such as Lesinurad, which was approved in the United States in 2015 and withdrawn from the market in 2019, and Dotinurad, which was launched in Japan.

[0005] Existing drugs and treatments have their limitations, and the vast majority of patients with hyperuricemia and gout have huge unmet clinical needs, so there is a need to develop safe and effective new uric acid-lowering drugs. From the perspective of mechanism of action and pharmacokinetics, using a single molecule to simultaneously attack the pathways of uric acid production (xanthine oxidase) and uric acid reabsorption (uric acid transporter URAT1, gene name SLC22A12) has more advantages than strategies that attack each pathway separately. Pfizer has developed a dual XOR / URAT1 inhibitor, the dual-target molecule PF-06743649, but it was stopped in Phase I clinical trials because a small number of patients developed acute kidney injury. Therefore, it is necessary to develop a new dual-target uric acid-lowering drug to benefit patients with hyperuricemia and reduce the burden on national medical expenses. Summary of the Invention

[0006] To address the above problems, the present invention provides a dihydrofuranoindole compound or its derivatives, which has good inhibitory activity on both urate oxidase and urate transporter, is a XOR / URAT1 dual inhibitor, and has a good uric acid-lowering effect.

[0007] The present invention includes the following technical solutions:

[0008] A dihydrofuranoindole compound having a structure as shown in Formula I or a derivative thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuterated compound thereof, or a tritiated compound thereof,

[0009] Wherein, X is selected from: O, S, C(R 1 )2、NR 2 ;

[0010] Z and W are independently selected from: CR 3 , N;

[0011] m and n are independently selected from: 0, 1, 2, 3, and m+n is 2, 3 or 4;

[0012] Q is selected from: hydrogen, one or more R 4 Substituted or unsubstituted C1-C6 alkyl, one or more R 4 Substituted or unsubstituted C1-C6 alkoxy, one or more R 4 Substituted or unsubstituted C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, one or more R 5 Substituted or unsubstituted C3-C8 cycloalkyl, one or more R 5 a substituted or unsubstituted 3-8 membered heterocyclic group, one or more R6 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 6 substituted or unsubstituted 5-10 membered heteroaryl,

[0013] L is selected from: hydrogen, one or more R 4 Substituted or unsubstituted C1-C6 alkyl, one or more R 4 Substituted or unsubstituted C1-C6 alkoxy, one or more R 4 Substituted or unsubstituted C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, one or more R 5 Substituted or unsubstituted C3-C8 cycloalkyl, one or more R 5 a substituted or unsubstituted 3-8 membered heterocyclic group, one or more R 6 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 6 substituted or unsubstituted 5-10 membered heteroaryl,

[0014] X 1 、X 2 are independently selected from: O, S, C(R 1 )2、NR 2 ;

[0015] Z 1 、Z 2 and Z 3 Independently selected from: CR 3 , N;

[0016] Each R 1 Each is independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and halogen;

[0017] Each R 2 are independently selected from: hydrogen, C1-C6 alkyl;

[0018] Each R 3 Each is independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and halogen;

[0019] Each R 4 Each of the following is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl;

[0020] Each R 5are independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl;

[0021] Each R 6 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, -C(=O)R, nitro, hydroxy, mercapto, amino, R 5 Substituted or unsubstituted C6-C 10 Aryl, R 5 substituted or unsubstituted 5-10 membered heteroaryl;

[0022] Each R is independently selected from the group consisting of hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino.

[0023] In some embodiments, the dihydrofuranoindole compound or its derivative has a structure as shown in Formula II:

[0024] In some embodiments, the dihydrofuranoindole compound or its derivative has a structure as shown in Formula III-1, Formula III-2, Formula III-3, Formula III-4, Formula III-5, Formula III-6, Formula III-7, Formula III-8, Formula III-9, Formula III-10, Formula III-11, Formula III-12, Formula III-13, Formula III-14, Formula III-15, Formula III-16, Formula III-17 or Formula III-18:

[0025] In some embodiments, each R in Formula III-1 1 Each R in Formula III-8, Formula III-9 and Formula III-10 is independently selected from: hydrogen, C1-C3 alkyl, halogen; 2 Each is independently selected from: hydrogen, C1-C3 alkyl.

[0026] In some embodiments, each R in Formula III-1 1 Each R in Formula III-8, Formula III-9 and Formula III-10 is independently selected from: hydrogen, methyl, ethyl, fluorine, chlorine, bromine; 2 are independently selected from the group consisting of: hydrogen, methyl, and ethyl.

[0027] In some embodiments, X 1 、X 2 are independently selected from: O, S, C(R 1)2、NR 2 ;

[0028] Z 1 、Z 2 and Z 3 Independently selected from: CR 3 , N;

[0029] Each R 1 Each is independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluorine, chlorine, and bromine;

[0030] Each R 2 are independently selected from: hydrogen, C1-C3 alkyl;

[0031] Each R 3 Each of the following is independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen.

[0032] In some embodiments, X 1 Selected from: O, S, X 2 NR 2 , R 2 Selected from: hydrogen, methyl, ethyl, propyl;

[0033] Z 1 、Z 2 and Z 3 One or two of them are N, and the others are CR 3 , R 3 Selected from: hydrogen, methyl, ethyl, propyl.

[0034] In some embodiments, each R 4 Each of the following groups is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclic group.

[0035] In some embodiments, each R 4 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxanyl, tetrahydropyrrolyl, and tetrahydrothiophenyl.

[0036] In some embodiments, each R 5 Each of the following is independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl.

[0037] In some embodiments, each R 5 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, and hydroxyl.

[0038] In some embodiments, each R 6 are independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, -C(=O)R, nitro, hydroxy, mercapto, amino, R 5 Substituted or unsubstituted phenyl, R 5 Substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 5-6 membered heteroaryl;

[0039] Each R is independently selected from the group consisting of hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkylamino.

[0040] In some embodiments, each R 6 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyacyl, ethoxyacyl, carbamoyl, nitro, hydroxyl, mercapto, amino, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, tetrazolyl, furyl, thienyl, pyrrolyl, and imidazolyl.

[0041] In some embodiments, Q is selected from: hydrogen, one or more R 4 Substituted or unsubstituted C1-C3 alkyl, one or more R 4 Substituted or unsubstituted C1-C3 alkoxy, one or more R 4 Substituted or unsubstituted C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, one or more R 5 Substituted or unsubstituted C3-C6 cycloalkyl, one or more R 5 a substituted or unsubstituted 3-6 membered heterocyclic group, one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6substituted or unsubstituted 5-6 membered heteroaryl,

[0042] X 1 、X 2 are independently selected from: O, S, C(R 1 )2、NR 2 ;

[0043] Z 1 、Z 2 and Z 3 Independently selected from: CR 3 , N;

[0044] Each R 1 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen;

[0045] Each R 2 are independently selected from: hydrogen, C1-C3 alkyl;

[0046] Each R 3 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen;

[0047] Preferably, each R 4 Each of the following is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclyl;

[0048] Preferably, each R 5 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl;

[0049] Preferably, each R 6 are independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, C(=O)R, nitro, hydroxy, mercapto, amino, R 5 Substituted or unsubstituted phenyl, R 5 Substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 5-6 membered heteroaryl;

[0050] Each R is independently selected from the group consisting of hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkylamino.

[0051] In some embodiments, Q is selected from hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, tetrahydropyrrolyl, tetrahydrothienyl, halogen-substituted tetrahydropyrrolyl, hydroxy-substituted tetrahydropyrrolyl, azetidinyl, halogen-substituted azetidinyl, hydroxy-substituted azetidinyl, one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6 Substituted or unsubstituted pyridyl, one or more R 6 Substituted or unsubstituted pyrazinyl, one or more R 6 Substituted or unsubstituted pyridazinyl, one or more R 6 substituted or unsubstituted pyrimidinyl,

[0052] Preferably, each R 6 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyacyl, ethoxyacyl, carbamoyl, nitro, hydroxyl, mercapto, amino, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, tetrazolyl, furyl, thienyl, pyrrolyl, and imidazolyl.

[0053] In some embodiments, Q is selected from: chlorine, bromine, aldehyde, cyano, difluoromethyl,

[0054] In some embodiments, Q is selected from the group consisting of chlorine, bromine, aldehyde, and cyano.

[0055] In some embodiments, Q is cyano.

[0056] In some embodiments, L is selected from: hydrogen, one or more R 4 Substituted or unsubstituted C1-C3 alkyl, one or more R 4 Substituted or unsubstituted C1-C3 alkoxy, one or more R 4 Substituted or unsubstituted C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, one or more R 5Substituted or unsubstituted C3-C6 cycloalkyl, one or more R 5 a substituted or unsubstituted 3-6 membered heterocyclic group, one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6 substituted or unsubstituted 5-6 membered heteroaryl,

[0057] X 1 、X 2 are independently selected from: O, S, C(R 1 )2、NR 2 ;

[0058] Z 1 , Z 2 and Z 3 Independently selected from: CR 3 , N;

[0059] Each R 1 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen;

[0060] Each R 2 are independently selected from: hydrogen, C1-C3 alkyl;

[0061] Each R 3 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen;

[0062] Preferably, each R 4 Each of the following is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclyl;

[0063] Preferably, each R 5 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl;

[0064] Preferably, each R 6 are independently selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, C(=O)R, nitro, hydroxy, mercapto, amino, R 5 Substituted or unsubstituted phenyl, R 5 Substituted or unsubstituted naphthyl, R 5substituted or unsubstituted 5-6 membered heteroaryl;

[0065] Each R is independently selected from the group consisting of hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkylamino.

[0066] In some embodiments, L is selected from hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxetanyl, tetrahydropyrrolyl, tetrahydrothienyl, halogen-substituted tetrahydropyrrolyl, hydroxy-substituted tetrahydropyrrolyl, azetidinyl, halogen-substituted azetidinyl, hydroxy-substituted azetidinyl, one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6 Substituted or unsubstituted pyridyl, one or more R 6 Substituted or unsubstituted pyrazinyl, one or more R 6 Substituted or unsubstituted pyridazinyl, one or more R 6 substituted or unsubstituted pyrimidinyl,

[0067] Preferably, each R 6 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyacyl, ethoxyacyl, carbamoyl, nitro, hydroxyl, mercapto, amino, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, tetrazolyl, furyl, thienyl, pyrrolyl, and imidazolyl.

[0068] In some embodiments, L is selected from:

[0069] In some embodiments, L is selected from:

[0070] In some embodiments, L is or

[0071] In some embodiments, Q is selected from: halogen, aldehyde, cyano, oxygen-containing 3-5 membered heterocyclic group;

[0072] L is selected from: 1 or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridyl, one or more R 6 Substituted or unsubstituted pyrazinyl, one or more R 6 substituted or unsubstituted pyrimidinyl, Among them, each R 6 Each is independently selected from the group consisting of hydrogen, methyl, ethyl, halogen, carboxyl, hydroxyl, tetrazolyl, and C(=O)NHOH.

[0073] In some embodiments, Q is selected from: chlorine, bromine, aldehyde, cyano,

[0074] L is selected from:

[0075] In some embodiments, Q is halogen, preferably chlorine or bromine;

[0076] L is selected from: 1 or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6 substituted or unsubstituted 5-6 membered heteroaryl,

[0077] Each R 6 Each of the following is independently selected from the group consisting of hydrogen, hydroxy, carboxyl, and tetrazolyl.

[0078] In some embodiments, Q is halogen, preferably chlorine or bromine; L is selected from: R 6 Substituted or unsubstituted phenyl, R 6 a substituted or unsubstituted pyridyl group.

[0079] In some embodiments, Q is halogen, preferably chlorine or bromine; L is selected from:

[0080] In some embodiments, Q is halogen, preferably chlorine or bromine; L is selected from:

[0081] In some embodiments, Q is halogen, preferably chlorine or bromine; L is or

[0082] In some embodiments, Q is cyano;

[0083] L is selected from: 1 or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6 substituted or unsubstituted 5-6 membered heteroaryl,

[0084] Each R 6 Each is independently selected from the group consisting of hydrogen, methyl, ethyl, hydroxy, carboxyl, halogen, tetrazolyl, and C(=O)NHOH.

[0085] In some embodiments, each R 6 Each is independently selected from the group consisting of hydrogen, hydroxy, carboxyl, tetrazolyl, and C(=O)NHOH.

[0086] In some embodiments, Q is cyano; L is selected from: one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridyl, one or more R 6 Substituted or unsubstituted pyrazinyl, one or more R 6 substituted or unsubstituted pyrimidinyl,

[0087] In some embodiments, Q is cyano; L is selected from: 1 or more R 6 Substituted or unsubstituted pyridyl, one or more R 6 substituted or unsubstituted pyrazinyl,

[0088] In some embodiments, Q is cyano; L is selected from:

[0089] In some embodiments, Q is cyano; L is selected from:

[0090] In some embodiments, Q is an aldehyde group;

[0091] L is selected from: 1 or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6 a substituted or unsubstituted 5-6 membered heteroaryl group;

[0092] Each R6 Each of the following is independently selected from the group consisting of hydrogen, hydroxy, carboxyl, and tetrazolyl.

[0093] In some embodiments, Q is an aldehyde group; L is selected from: one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridyl, one or more R 6 a substituted or unsubstituted pyrimidinyl group.

[0094] In some embodiments, Q is an aldehyde group; L is selected from:

[0095] In some embodiments, Q is an aldehyde group; L is selected from:

[0096] The present invention also provides the use of the dihydrofuranoindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, including the following technical solutions:

[0097] Use of the dihydrofuranoindole compounds or their derivatives, stereoisomers, pharmaceutically acceptable salts, solvates, prodrug molecules, deuterated compounds, or tritiated compounds of the present invention in the preparation of XOR inhibitors and / or URAT1 inhibitors.

[0098] The dihydrofuranoindole compounds or their derivatives, stereoisomers, pharmaceutically acceptable salts, solvates, prodrug molecules, deuterated compounds, or tritiated compounds of the present invention are used in the preparation of uric acid-lowering drugs.

[0099] The present invention relates to the use of the dihydrofuranoindole compounds or their derivatives, stereoisomers, pharmaceutically acceptable salts, solvates, prodrug molecules, deuterated compounds, or tritiated compounds in the preparation of drugs for preventing and / or treating gout or hyperuricemia.

[0100] The present invention also provides an XOR / URAT1 dual inhibitor, the active ingredient of which contains the dihydrofuranoindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated product, or its tritiated product according to the present invention.

[0101] The present invention also provides a uric acid-lowering drug, characterized in that it is prepared from an active ingredient and a pharmaceutically acceptable carrier or excipient, wherein the active ingredient includes the dihydrofuranoindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated product, or its tritiated product according to the present invention.

[0102] The present invention also provides a method for preventing and / or treating gout or hyperuricemia, comprising:

[0103] Administering a safe and effective amount of the dihydrofuranoindole compound of the present invention or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated product, or its tritiated product to a patient with gout or hyperuricemia; and / or,

[0104] A safe and effective amount of the uric acid-lowering drug of the present invention is administered to patients with gout or hyperuricemia.

[0105] The dihydrofuranoindole compounds or their derivatives provided by the present invention are a class of compounds with novel structures. These compounds have good inhibitory activity against both urate oxidase and urate transporter, are a type of XOR / URAT1 dual inhibitor, have good uric acid-lowering effects, are safe, have excellent pharmacokinetic properties, and are highly druggable. They can be used to prepare uric acid-lowering drugs for the prevention and / or treatment of gout or hyperuricemia. BRIEF DESCRIPTION OF THE DRAWINGS

[0106] FIG1 shows the blood uric acid concentration of mice 8 hours after administration of compound 4, compound 12, and compound 137-7. DETAILED DESCRIPTION

[0107] To facilitate understanding of the present invention, the present invention will be described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the present disclosure more thorough and comprehensive.

[0108] In the following examples, the experimental methods without specific conditions are generally carried out under conventional conditions or conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0109] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which this invention pertains. The terms used in this specification are for the purpose of describing specific embodiments only and are not intended to limit the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0110] Furthermore, as used herein, the term "or" is inclusive and equivalent to the term "and / or," unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for being based on other factors not described, unless the context clearly dictates otherwise. Furthermore, throughout this specification, the meanings of "a," "an," and "the" include plural referents. The meaning of "in" includes "in" and "on."

[0111] In the compounds of the present invention, when any variable (such as R 4 、R 5 If a substituent (e.g., ) occurs more than once in any component, its definition at each occurrence is independent of its definition at every other occurrence. Likewise, combinations of substituents and variables are permissible so long as such combinations result in a stable compound. A line drawn from a substituent into the ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that such bonds may be attached only to any suitable carbon atom in an adjacent ring. It will be understood that one of ordinary skill in the art can select substituents and substitution patterns in the compounds of the present invention to provide compounds that are chemically stable and readily synthesized from readily available starting materials using techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it will be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0112] As used herein, the term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, the definition of "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0113] The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon group whose ring atoms are composed of carbon atoms, and the bicyclic or polycyclic rings include spirocyclic, fused rings and bridged rings. For example, "cycloalkyl" includes but is not limited to the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wait.

[0114] The term "alkoxy" used herein refers to a group having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc.

[0115] As used herein, the term "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic substituent, wherein one or more ring atoms are selected from N, O or S(O)m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon, and the bicyclic or polycyclic rings include spirocyclic, fused and bridged rings. For example: oxetanyl, azetidinyl, morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothienyl, etc., and N-oxides thereof. Attachment of the heterocyclic substituents can be achieved via a carbon atom or via a heteroatom.

[0116] As used herein, the term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N, or S. The aromatic ring may be monocyclic, bicyclic, or polycyclic, and includes, but is not limited to, quinolinyl, pyrazolyl, pyrrolyl, thienyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, and pyridazinyl. "Heteroaryl" is also understood to include any nitrogen-containing heteroaryl N-oxide derivative. Attachment of the heteroaryl group may be through a carbon atom or a heteroatom.

[0117] As will be understood by those skilled in the art, "halo" or "halo" as used herein refers to chlorine, fluorine, bromine and iodine.

[0118] The present invention includes the free forms of the compounds of Formula I, as well as pharmaceutically acceptable salts and stereoisomers thereof. Pharmaceutically acceptable salts encompassed include not only the exemplary salts of the specific compounds described herein, but also representative pharmaceutically acceptable salts of the free forms of all compounds of Formula I. The free forms of specific salts of the compounds described can be isolated using techniques known in the art. Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric amount or an excess of the desired salt form of an inorganic or organic acid in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0119] Therefore, pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts of the compounds of this invention formed by reacting an alkaline compound of this invention with an inorganic or organic acid. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.

[0120] If the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0121] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '1977: 66: 1-19, describes in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

[0122] The metabolites of the compounds of the present invention and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds of the present invention and their pharmaceutically acceptable salts in vivo, are also included in the claims of the present invention.

[0123] The present invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective amount, and a pharmaceutically acceptable carrier or excipient.

[0124] The "active ingredient" described in the present invention refers to the compound of formula I described in the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or a solvate thereof.

[0125] A "safe and effective amount" refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, a pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably 10-200 mg per dose. Preferably, "one dose" is one tablet.

[0126] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0127] "Pharmaceutically acceptable carrier or excipient" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be sufficiently pure and have sufficiently low toxicity.

[0128] "Compatibility" herein means that the components in the composition can be blended with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.

[0129] Examples of pharmaceutically acceptable carriers or excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0130] In another preferred embodiment, the compound of formula I of the present invention can form a complex with a macromolecular compound or polymer through non-bonding interaction. In another preferred embodiment, the compound of formula I of the present invention, as a small molecule, can also be linked to a macromolecular compound or polymer through a chemical bond. The macromolecular compound can be a biological macromolecule such as a polysaccharide, protein, nucleic acid, polypeptide, etc.

[0131] There is no particular limitation on the administration of the active ingredient or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.

[0132] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0133] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with:

[0134] (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;

[0135] (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

[0136] (c) humectants, for example, glycerin;

[0137] (d) disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0138] (e) buffering solvents, such as paraffin;

[0139] (f) absorption accelerators, for example, quaternary ammonium compounds;

[0140] (g) wetting agents, such as cetyl alcohol and glyceryl monostearate;

[0141] (h) adsorbents, for example, kaolin; and

[0142] (i) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffering agent.

[0143] The solid dosage forms can also be prepared using coatings and shells, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a certain portion of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes.

[0144] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0145] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0146] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0147] The compounds of the present invention may be administered alone or in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the original drug's route of administration and dosage remain unchanged, while the compound of Formula I is administered simultaneously or subsequently. When the compound of Formula I is administered concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of Formula I is preferably used. Combination administration also includes administering the compound of Formula I and one or more other known drugs during overlapping time periods. When the compound of Formula I is administered in combination with one or more other drugs, the dosage of the compound of Formula I or the known drug may be lower than when administered alone.

[0148] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0149] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0150] The starting materials in the following examples can be obtained from commercial sources, or prepared by methods known in the art, or prepared according to the methods described herein.

[0151] Example 1 Preparation of Compound 1

[0152] Step 1: Synthesis of 6-bromo-5-amino-1,3-dihydroisobenzofuran (Intermediate 1-1)

[0153] 5-Amino-1,3-dihydroisobenzofuran (20 g, 0.148 mol) and NBS (26.2 g, 0.148 mol) were added to acetonitrile (300 ml), and the mixture was stirred at 0°C for 4 hours. After concentration, water was added to the reaction mixture, and dichloromethane was added for extraction. The organic phase was dried and concentrated under reduced pressure to obtain an off-white solid product (30.6 g, 97%).

[0154] MS(ESI)calcd for C8H8BrNO:212.98; found:213.85, 215.85[M+1].

[0155] 1 H NMR (400MHz, CDCl3) δ7.28 (s, 1H), 6.64 (s, 1H), 4.97 (d, J = 1.2Hz, 2H), 4.99 (d, J = 1.2Hz, 2H), 4.08 (brs, 2H).

[0156] Step 2: Synthesis of 6-trimethylsilylene-5-amino-1,3-dihydroisobenzofuran (Intermediate 1-2)

[0157] 6-Bromo-5-amino-1,3-dihydroisobenzofuran (20 g, 93.9 mmol), trimethylsilylene (18.45 g, 187.8 mmol), CuI (894 mg, 4.7 mmol), and Pd(dppf)Cl2 (2.1 g, 2.82 mmol) were added to triethylamine (190 ml). The reaction was then allowed to react at 100°C for 12 hours. After concentration, the reaction mixture was treated with water and extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain the product as a yellow solid (17.4 g, 80.5%).

[0158] MS(ESI)calcd for C 13 H 17 NOSi:231.11; found:232.00[M+1].

[0159] 1 H NMR (400MHz, CDCl3) δ7.15(s,1H),6.56(s,1H),4.98(s,2H),4.96(s,2H),4.25(brs,2H),0.26(s,9H).

[0160] Step 3: Synthesis of 5,7-dihydro-1H-furo[3,4-f]indole (Intermediate 1-3)

[0161] 6-Trimethylsilylene-5-amino-1,3-dihydroisobenzofuran (15 g, 64.8 mmol) and CuI (24.7 g, 130 mmol) were added to DMF (130 ml). The reaction was then allowed to react at 120°C for 1 hour. After concentration, the reaction mixture was treated with water and extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain a yellow solid product (5.2 g, 50.5%).

[0162] MS(ESI)calcd for C 10 H9NO:159.07; found:216.00[M+1].

[0163] 1 H NMR (400MHz, CDCl3) δ8.15(brs,1H),7.45(s,1H),7.26(s,1H),7.22-7.20(m,1H),6.53-6.52(m,1H),5.19(s,4H).

[0164] Step 4: Synthesis of 3-chloro-5,7-dihydro-1H-furo[3,4-f]indole (Intermediate 1-4)

[0165] 5,7-Dihydro-1H-furo[3,4-f]indole (400 mg, 2.5 mmol) and NCS (355 mg, 2.5 mmol) were added to dichloromethane (10 ml). The mixture was allowed to react at room temperature for 0.5 hours. Water was then added to the reaction mixture, and ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain the product as a yellow solid (288 mg, 60%).

[0166] 1 H NMR (400MHz, CDCl3) δ8.08(brs,1H),7.45(s,1H),7.19(s,1H),7.17(d,J=2.8Hz,1H),5.19(s,2H),5.18(s,2H).

[0167] Step 5: Synthesis of ethyl 4-(3-chloro-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyleneoxy)benzoate (Intermediate 1-5)

[0168] 3-Chloro-5,7-dihydro-1H-furo[3,4-f]indole (230 mg, 1.2 mmol), Cs2CO3 (970 mg, 2.98 mmol), and ethyl 4-fluoro-2-(methoxymethyleneoxy)benzoate were added to DMF (5 ml). The reaction was then allowed to react at 80°C for 12 hours, then cooled to room temperature. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield an off-white solid (430 mg, 89%).

[0169] 1 H NMR (400MHz, CDCl3) δ7.96(d,J=8.4Hz,1H),7.50(s,1H),7.42(s,1H),7.34(s,1H),7.31(d,J=2Hz,1H),7.16(dd,J=8.4and 2.0Hz,1H),5.30(s,2H),5.21(s,2H),5.17(s,2H),4.40(q,J=7.2Hz,2H),3.55(s,3H),1.41(t,J=7.2Hz,3H).

[0170] Step 6: Synthesis of ethyl 4-(3-chloro-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (Intermediate 1-6)

[0171] To THF (4 ml), add ethyl 4-(3-chloro-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyleneoxy)benzoate (430 mg, 1.2 mmol), EtOH (2 ml), and HCl (2.0 M, 2 ml). The mixture was reacted at 65°C for 1 hour, then cooled to room temperature. The product was filtered, washed with EtOH and H2O, and dried to give an off-white solid (254 mg, 66%).

[0172] 1 H NMR (400MHz, DMSO-D6) δ10.85(s,1H),7.98(s,1H),7.95(d,J=8.4Hz,1H),7.66(s,1H),7.51(s, 1H),7.25-7.22(m,2H),5.09(s,2H),5.08(s,2H),4.40(q,J=7.2Hz,2H),1.37(t,J=7.2Hz,3H).

[0173] Step 7: Synthesis of 4-(3-chloro-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoic acid (Compound 1)

[0174] To THF (7 ml), ethyl 4-(3-chloro-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (230 mg, 0.7 mmol), H₂O (3.5 ml), and LiOH (298 mg, 7.1 mmol) were added. The mixture was allowed to react at room temperature for 48 hours. HCl (2.0 M) was then added to acidify the pH of the reaction solution to 2. Ethyl acetate was then added for extraction. The organic phase was washed with H₂O, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to afford an off-white solid product (205 mg, 97%).

[0175] MS(ESI)calcd for C 17 H 12 ClNO4:329.05; found:328.05[M-1].

[0176] 1 H NMR (400MHz, DMSO-D6) δ7.99 (s, 1H), 7.96 (d, J = 8.4Hz, 1H), 7.67 (s, 1H), 7.50 (s, 1H), 7.22-7.19 (m, 2H), 5.09 (s, 4H).

[0177] Example 2 Preparation of Compound 12

[0178] Step 1: Synthesis of methyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyleneoxy)benzoate (Intermediate 12-1)

[0179] The synthesis of compound 3-cyano-5,7-dihydro-1H-furo[3,4-f]indole (Intermediate 4-2) is shown in Example 3.

[0180] 3-Cyano-5,7-dihydro-1H-furo[3,4-f]indole (80 mg, 0.43 mmol), Cs2CO3 (354 mg, 1.08 mmol), and methyl 4-fluoro-2-(methoxymethyleneoxy)benzoate (140 mg, 0.65 mmol) were added to DMF (2.5 ml). The reaction was then allowed to react at 85°C for 12 hours, then cooled to room temperature. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield an off-white solid (70 mg, 43%).

[0181] 1H NMR (400MHz, CDCl3) δ7.99(d,J=8.4Hz,1H),7.82(s,1H),7.65(s,1H),7.40(s,1H),7.35(d,J=2.0Hz,1H),7.18(dd,J=8.4and 2.0Hz,1H),5.32(s,2H),5.22(s,2H),5.17(s,2H),3.95(s,3H),3.55(s,3H).

[0182] Step 2: Synthesis of methyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (Intermediate 12-2)

[0183] Methyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyleneoxy)benzoate (65 mg, 0.17 mmol), EtOH (2 ml), and HCl (2.0 M, 0.5 ml) were added to THF (1 ml). The reaction was then incubated at 70°C for 4 hours, cooled to room temperature, filtered, washed with EtOH and H₂O, and dried to yield an off-white solid (40 mg, 70%).

[0184] 1 H NMR (400MHz, DMSO-D6) δ10.80(s,1H),8.64(s,1H),7.97(d,J=8.4Hz,1H),7.65(s,2H),7.28(d,J=2.0Hz,1H),7.25(dd,J=8.4and 2.0Hz,1H),5.09(s,2H),5.06(s,2H),3.92(s,3H).

[0185] Step 3: Synthesis of 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoic acid (Compound 12)

[0186] Methyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (420 mg, 1.2 mmol), H₂O (6.0 ml), and LiOH (506 mg, 12.1 mmol) were added to THF (15 ml). The reaction was allowed to react at room temperature for 48 hours. HCl (2.0 M) was then added to acidify the reaction solution to pH 2. The off-white solid product was filtered, washed with H₂O and EtOH, and dried to obtain the desired product (225 mg, 59%).

[0187] MS(ESI)calcd for C 18 H12 N2O4:320.08; found:318.85[M-1].

[0188] 1 H NMR (400MHz, DMSO-D6) δ8.64(s,1H),8.00(d,J=8.4Hz,1H),7.67(s,1H),7.66(s,1H),7.27(d,J=2.0Hz,1H),7.24(dd,J=8.4and 2.4Hz,1H),5.10(s,2H),5.07(s,2H).

[0189] Example 3 Preparation of Compound 4

[0190] Step 1: Synthesis of 3-formyl-5,7-dihydro-1H-furo[3,4-f]indole (Intermediate 4-1)

[0191] 5,7-Dihydro-1H-furo[3,4-f]indole (131 mg, 0.82 mmol) and POCl3 (152 mg, 0.99 mmol) were added to DMF (1.5 ml). The mixture was allowed to react at room temperature for 3 hours. A 2.0 M aqueous NaOH solution was then added to adjust the pH to 11-12, and the reaction mixture was heated to 70°C for 0.5 hours. The mixture was extracted with ethyl acetate, and the organic phase was dried, concentrated under reduced pressure, and spin-dried to give the product as a red solid (80 mg, 51%).

[0192] 1 H NMR (400MHz, DMSO-D6) δ12.11(brs,1H),9.89(s,1H),8.25(d,J=3.2Hz,1H),7.95(s,1H),7.39(s,1H),5.05(s,4H).

[0193] Step 2: Synthesis of 3-cyano-5,7-dihydro-1H-furo[3,4-f]indole (Intermediate 4-2)

[0194] 3-Formyl-5,7-dihydro-1H-furo[3,4-f]indole (80 mg, 0.42 mmol), hydroxylamine hydrochloride (60 mg, 0.84 mmol), and pyridine (0.2 ml) were added to THF (1.5 ml). The reaction was then allowed to react at 80°C for 4 hours. Acetic anhydride (0.4 ml) was then added and allowed to react for 12 hours. Aqueous NaOH (2.0 M) was then added at room temperature to adjust the pH of the reaction solution to 11-12. The mixture was extracted with ethyl acetate, and the organic phase was dried, concentrated under reduced pressure, and spun down to afford the product as a yellow solid (70 mg, 90%).

[0195] Step 3: Synthesis of ethyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-benzoate (Intermediate 4-3)

[0196] 3-Cyano-5,7-dihydro-1H-furo[3,4-f]indole (200 mg, 1.1 mmol), Cs2CO3 (885 mg, 2.72 mmol), and ethyl 4-fluorobenzoate (274 mg, 1.63 mmol) were added to DMF (4 ml). The reaction was then allowed to react at 80°C for 12 hours, then cooled to room temperature. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield an off-white solid product (189 mg, 52%).

[0197] MS(ESI)calcd for C 20 H 16 N2O3:332.12; found:333.00[M+1].

[0198] 1 H NMR (400MHz, CDCl3) δ8.27(d,J=8.4Hz,2H),7.82(s,1H),7.66(s,1H),7.57(d,J=8.4Hz 2H),7.39(s,1H),5.23(s,2H),5.17(s,2H),4.45(q,J=7.2Hz,2H),1.44(t,J=7.2Hz,3H).

[0199] Step 4: Synthesis of 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-benzoic acid (Compound 4)

[0200] To THF (2 ml), ethyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)benzoate (90 mg, 0.27 mmol), H₂O (1.0 ml), and LiOH (68 mg, 1.63 mmol) were added. The reaction was allowed to react at room temperature for 48 hours. HCl (2.0 M) was then added to acidify the reaction solution to pH 2. The off-white solid product was filtered, washed with H₂O and EtOH, and dried to yield the desired product (55 mg, 67%).

[0201] MS(ESI)calcd for C 18 H 12 N2O3:304.08; found:302.95[M-1].

[0202] 1H NMR (400MHz, DMSO-D6) δ13.22(brs,1H),8.66(s,1H),8.16(d,J=8.4Hz,2H) ,7.81(d,J=8.4Hz,2H),7.67(s,1H),7.64(s,1H),5.11(s,2H),5.07(s,2H).

[0203] Example 4 Preparation of Compound 2

[0204] Step 1: Synthesis of ethyl 4-(3-formyl-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyleneoxy)benzoate (Intermediate 2-1)

[0205] 3-Formyl-5,7-dihydro-1H-furo[3,4-f]indole (200 mg, 1.07 mmol), Cs2CO3 (870 mg, 2.67 mmol), and ethyl 4-fluoro-2-(methoxymethyleneoxy)benzoate (366 mg, 1.6 mmol) were added to DMF (3.0 ml). The reaction was then allowed to react at 80°C for 12 hours, then cooled to room temperature. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column (Hexane / EtOAc = 3 / 2) to yield the product as an off-white solid (210 mg, 50%).

[0206] 1 H NMR (400MHz, CDCl3) δ10.11(s,1H),8.23(s,1H),8.00(d,J=8.4Hz,1H),7.93(s,1H),7.38(d,J=2.0Hz,1H),7.37(s,1H),7.22(dd,J=2.0and 8.0Hz,1H),5.32(s,2H),5.22(s,2H),5.17(s,2H),4.42(q,J=7.2Hz,2H),3.55(s,3H),1.42(t,J=7.2Hz,3H).

[0207] Step 2: Synthesis of methyl 4-(3-formyl-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (Intermediate 2-2)

[0208] To THF (2 ml), add ethyl 4-(3-formyl-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyleneoxy)benzoate (160 mg, 0.40 mmol), EtOH (1.0 ml), and HCl (2.0 M, 1.0 ml). The mixture was reacted at 70°C for 2 hours, then cooled to room temperature. The product was filtered, washed with EtOH and H2O, and dried to give an off-white solid (108 mg, 76%).

[0209] 1 H NMR(400MHz,DMSO-D6)δ10.87(s,1H),10.03(s,1H),8.66(s,1H),8.10(s,1H) ,8.01(d,J=8.4Hz,1H),7.61(s,1H),7.33(d,J=2.0Hz,1H),7.30(dd,J=2.0and 8.4Hz,1H),5.10(s,2H),5.07(s,2H),4.41(q,J=7.2Hz,2H),1.37(t,J=7.2Hz,3H).

[0210] Step 3: Synthesis of 4-(3-formyl-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoic acid (Compound 2)

[0211] To THF (4 ml) was added ethyl 4-(3-formyl-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (250 mg, 0.71 mmol), H₂O (2.0 ml), and LiOH (180 mg, 4.3 mmol). The reaction was allowed to proceed at room temperature for 48 hours. HCl (2.0 M) was then added to acidify the reaction solution to pH 2. The off-white solid product was filtered, washed with H₂O and EtOH, and dried to yield the desired product (219 mg, 95%).

[0212] MS(ESI)calcd for C 18 H 13 NO5:323.08; found:322.05[M-1].

[0213] 1 H NMR (400MHz, DMSO-D6) δ10.02(s,1H),8.66(s,1H),8.10(s,1H),8.02(d,J=8.4Hz,1H),7.62(s,1H),7.30-7.26(m,2H),5.10(s,2H),5.07(s,2H).

[0214] Example 5 Preparation of Compound 21

[0215] Step 1: Synthesis of 1-Boc-3-iodo-5,7-dihydro-1H-furo[3,4-f]indole (Intermediate 21-1)

[0216] 5,7-Dihydro-1H-furo[3,4-f]indole (500 mg, 3.18 mmol), I2 (848 mg, 3.34 mmol), and KOH (268 mg, 4.77 mmol) were added to DMF (10 ml). The mixture was allowed to react at room temperature for 4 hours. Saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 were then added for extraction. The organic phase was dried, concentrated under reduced pressure, and then spin-dried. Dichloromethane (5 ml), DMAP (40.0 mg, 0.32 mmol), and Boc-anhydride (1.04 g, 4.77 mmol) were then added. The mixture was allowed to react at room temperature for 4 hours. Saturated aqueous NaHCO3 was then added for extraction. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield an off-white solid (830 mg, 65%).

[0217] MS(ESI)calcd for C 15 H 16 INO3:385.02; found:385.95[M+1].

[0218] 1 H NMR (400MHz, CDCl3) δ8.02(s,1H),7.70(s,1H),7.23(s,1H),5.20(s,4H),1.66(s,9H).

[0219] Step 2: Synthesis of methyl 4-(1-N-Boc-5,7-dihydro-1H-furo[3,4-f]indol-3-yl)-2-(methoxymethyleneoxy)benzoate (Intermediate 21-2)

[0220] To DMF (5 ml) were added 1-Boc-3-iodo-5,7-dihydro-1H-furo[3,4-f]indole (820 mg, 2.06 mmol), Na₂CO₃ (1.0 N, 4.2 ml, 4.2 mmol), Pd(PPh₃)₄ (238 mg, 0.21 mmol), and 3-(methoxymethyleneoxy)-4-methoxycarbonylphenylboronic acid pinesyl ester (1.04 g, 3.08 mmol). The reaction was then incubated at 80°C for 12 hours and cooled to room temperature. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure to dryness, and then filtered through a column to yield the product as an off-white solid (320 mg, 34%).

[0221] MS(ESI)calcd for C 25 H 27 NO7:453.18; found:454.10[M+1].

[0222] 1 H NMR (400MHz, CDCl3) δ8.11(s,1H),7.91(d,J=8.0Hz,1H),7.74(s,1H),7.60(s,1H),7.45(d,J=1.6Hz,1H),7 .31(dd,J=1.6Hz,8.0Hz,1H),5.33(s,2H),5.23(s,2H),5.20(s,2H),3.93(s,3H),3.56(s,3H),1.70(s,9H).

[0223] Step 3: Synthesis of methyl 4-(5,7-dihydro-1H-furo[3,4-f]indol-3-yl)-2-(methoxymethyleneoxy)benzoate (Intermediate 21-3)

[0224] To MeOH (30 ml), add methyl 4-(1-N-Boc-5,7-dihydro-1H-furo[3,4-f]indol-3-yl)-2-(methoxymethyleneoxy)benzoate (1.4 g, 3.09 mmol) and a 0.1 M KOH methanol solution (90 ml). The mixture was reacted at 60°C for 1 hour and then cooled to room temperature. Water was then added to the reaction mixture, and extraction was performed with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then spun down to dryness to afford the product as a brown solid (1.05 g, 96%).

[0225] 1 H NMR (400MHz, CDCl3) δ8.41(s,1H),7.90(d,J=8.0Hz,1H),7.74(s,1H),7.49(d,J=1.2Hz,1H),7.45(d,J=2.4Hz,1H),7.34(dd,J=1.6and 8.0Hz,1H),5.33(s,2H),5.21(s,4H),3.92(s,3H),3.57(s,3H).

[0226] Step 4: Synthesis of methyl 4-{N-(oxetan-3-yl)-5,7-dihydro-1H-furo[3,4-f]indol-3-yl}-2-(methoxymethyleneoxy)benzoate (Intermediate 21-4)

[0227] To DMF (1.5 ml) was added methyl 4-(5,7-dihydro-1H-furo[3,4-f]indol-3-yl)-2-(methoxymethyleneoxy)benzoate (130 mg, 0.37 mmol), Cs2CO3 (300 mg, 0.92 mmol), and 3-iodooxetane (101 mg, 0.55 mmol). The reaction was then incubated at 80°C for 12 hours and cooled to room temperature. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure to dryness, and then filtered through a column to yield an off-white solid (68 mg, 45%).

[0228] 1 H NMR (400MHz, CDCl3) δ7.91(d,J=8.0Hz,1H),7.75(s,1H),7.63(s,1H),7.47(s,1H),7.37(s,1H),7.34(d,J= 8.0Hz,1H),5.62-5.55(m,1H),5.34(s,2H),5.24-5.20(m,6H),5.15-5.11(m,2H),3.92(s,3H),3.57(s,3H).

[0229] Step 5: Synthesis of 4-{N-(oxetan-3-yl)-5,7-dihydro-1H-furo[3,4-f]indol-3-yl}-2-(methoxymethyleneoxy)benzoic acid (Compound 21)

[0230] To THF (1.0 ml) was added methyl 4-{N-(oxetan-3-yl)-5,7-dihydro-1H-furo[3,4-f]indol-3-yl}-2-(methoxymethyleneoxy)benzoate (35 mg, 0.08 mmol), H₂O (0.5 ml), and LiOH (36 mg, 0.85 mmol). The reaction was allowed to react at room temperature for 24 hours. HCl (2.0 M) was then added to acidify the reaction solution to pH 2. The mixture was extracted with ethyl acetate, and the organic phase was dried, concentrated under reduced pressure, and spun down to afford the desired product (25 mg, 76%) as an off-yellow solid.

[0231] MS(ESI)calcd for C 22 H 21 NO6:395.14; found:396.10[M+1].

[0232] 1H NMR (400MHz, DMSO-D6) δ12.52(brs,1H),8.26(s,1H),7.82(s,1H),7.78(d,J=8.0Hz,1H),7.53(s,1H),7.50(d,J=1.2Hz,1H),7.46(dd,J=1.6and 8.0Hz,1H),5.81(pet,J=7.2Hz,1H),5.37(s,2H),5.09(s,4H),5.08-5.05(m,2H),5.03-5.00(m,2H),3.46(s,3H).

[0233] Example 6 Preparation of Compound 24

[0234] Step 1: Synthesis of ethyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyleneoxy)benzoate (Intermediate 24-1)

[0235] To 30 ml of DMF, add 3-cyano-5,7-dihydro-1H-furo[3,4-f]indole (2.0 g, 10.86 mmol), Cs2CO3 (8.8 g, 27.2 mmol), and ethyl 4-fluoro-2-(methoxymethyleneoxy)benzoate (3.7 g, 16.29 mmol). The reaction was then allowed to react at 85°C for 12 hours, then cooled to room temperature. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield an off-white solid (1.2 mg, 28%).

[0236] Step 2: Synthesis of 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyleneoxy)benzoic acid (Intermediate 24-2)

[0237] Ethyl 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyleneoxy)benzoate (1.2 g, 3.06 mmol), H₂O (8.0 ml), and LiOH (770 mg) were added to THF (16 ml). The mixture was allowed to react at room temperature for 48 hours. HCl (2.0 M) was then added to acidify the pH of the reaction solution to 2. The off-white solid product was filtered, washed with H₂O and EtOH, and dried to obtain the desired product (0.8 g, 72%).

[0238] Step 3: Synthesis of 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyleneoxy)-N-(OTHP)benzamide (Compound 24-3)

[0239] 4-(3-Cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyleneoxy)benzoic acid (1.2 g, 3.3 mmol), DIPEA (1.28 g), HATU (2.5 g, 6.6 mmol), and NH2OTHP (580 mg, 4.95 mmol) were added to DMF (8 ml). The mixture was allowed to react at room temperature for 20 hours. Water was then added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain an off-white solid product (1.1 g, 72%).

[0240] 1 H NMR (400MHz, CDCl3) δ10.24(s,1H),8.38(d,J=8Hz,1H),7.81(s,1H),7.64(s,1H),7.38(s,1H),7.32(d,J=2.0Hz,1H),7.29(dd,J=8.4and 2.0Hz,1H),5.40(s,2H),5.22(s,2H),5.17(s,2H),5.12(d,J=3.2Hz,1H),4.09-4 .03(m,1H),3.70-3.67(m,1H),3.57(s,3H),1.95-1.88(m,3H),1.71-1.64(m,3H).

[0241] Step 4: Synthesis of 4-(3-cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-N,2-dihydroxybenzamide (Intermediate 24-4)

[0242] 4-(3-Cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyleneoxy)-N-(OTHP)benzamide (1.1 g, 2.37 mmol), EtOH (6 ml), and HCl (2.0 M, 7 ml) were added to THF (12 ml). The mixture was then reacted at 70°C for 4 hours and cooled to room temperature. The resulting solid was filtered, washed with EtOH and H2O, and dried to yield the product as an off-white solid (0.8 g, 99%).

[0243] MS(ESI)calcd for C 18 H 13 N3O4:335.09; found:333.90[M-1].

[0244] 1H NMR (400MHz, DMSO-D6) δ12.69(brs,1H),11.58(s,1H),8.59(s,1H),7.90(d,J=8. 8Hz,1H),7.64(s,1H),7.62(s,1H),7.19-7.16(m,2H),5.08(s,2H),5.06(s,2H).

[0245] Step 5: Synthesis of 1-(benzo[d]isoxazol-3(2H)-on-6-yl)-3-cyano-5,7-dihydro-1H-furo[3,4-f]indole (Compound 24)

[0246] 4-(3-Cyano-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-N,2-dihydroxybenzamide (300 mg, 0.9 mmol) and CDI (218 mg) were added to THF (9 ml), and the mixture was reacted at 70°C for 4 hours. Water was then added to the reaction mixture, and ethyl acetate was added for extraction. The mixture was washed with HCl (1 M), dried, concentrated under reduced pressure, and then passed through a column to give an off-white solid product (115 mg, 40%).

[0247] MS(ESI)calcd for C 18 H 11 N3O3:317.08; found:315.95[M-1].

[0248] 1 H NMR (400MHz, DMSO-D6) δ12.69(brs,1H),11.29(s,1H),8.59(s,1H),8.16(d,J=8.4Hz,1H),7.86(d,J=2Hz,1H),7.76(dd,J=8.4and 2.0Hz,1H),7.71(s,1H),7.68(s,1H),5.10(s,2H),5.07(s,2H).

[0249] Example 7 Preparation of Compound 59

[0250] Step 1: Synthesis of 5-iodo-6-amino-2,3-dihydrobenzofuran (Intermediate 59-1)

[0251] 6-Amino-2,3-dihydrobenzofuran (0.9 g, 6.66 mmol) and NIS (1.95 g, 8.66 mmol) were added to acetonitrile (12 ml), and the mixture was stirred at 0°C for 4 hours. After concentration, water was added to the reaction mixture, and dichloromethane was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then passed through a column to obtain a yellowish solid product (1.47 g, 86%).

[0252] 1 H NMR (400MHz, CDCl3) δ7.39 (s, 1H), 6.27 (s, 1H), 4.53 (t, J = 8.4Hz, 2H), 4.01 (s, 2H), 3.10 (t, J = 8.4Hz, 2H).

[0253] Step 2: Synthesis of 5-trimethylsilylene-6-amino-2,3-dihydrobenzofuran (Intermediate 59-2)

[0254] 5-iodo-6-amino-2,3-dihydrobenzofuran (1.5 g, 5.75 mmol), trimethylsilylene (2.8 g, 28.74 mmol), CuI (2.2 g, 11.5 mmol), and Pd(dppf)Cl2 (1.3 g, 1.73 mmol) were added to triethylamine (19 ml). The reaction was then allowed to react at 100°C for 24 hours. After concentration, the reaction mixture was treated with water and extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain the product as a yellow solid (1.3 g, 98%).

[0255] 1 H NMR (400MHz, CDCl3) δ7.10 (s, 1H), 6.15 (s, 1H), 4.53 (t, J = 8.4Hz, 2H), 4.20 (s, 2H), 3.06 (t, J = 8.4Hz, 2H), 0.24 (m, 9H).

[0256] Step 3: Synthesis of 3,7-dihydro-2H-furo[3,2-f]indole (Intermediate 59-3)

[0257] 5-Trimethylsilylene-6-amino-2,3-dihydrobenzofuran (1.3 g, 5.63 mmol) and CuI (1.6 g, 8.44 mmol) were added to DMF (26 ml). The reaction was then allowed to react at 120°C for 2 hours. After concentration, the reaction mixture was treated with water and extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain a yellow solid product (292 mg, 32%).

[0258] 1 H NMR (400MHz, CDCl3) δ7.96(brs,1H),7.39(s,1H),7.06-7.04(m,1H),6.79(s,1H),6.44-6.42(m,1H),4.60(t,J=8.4Hz,2H),3.27(t,J=8.4Hz,2H).

[0259] Step 4: Synthesis of 5-formyl-3,7-dihydro-2H-furo[3,2-f]indole (Intermediate 59-4)

[0260] 3,7-Dihydro-2H-furo[3,2-f]indole (80 mg, 0.5 mmol) and POCl3 (93 mg, 0.6 mmol) were added to DMF (1.5 ml). The mixture was allowed to react at room temperature for 3 hours. A 2.0 M aqueous NaOH solution was then added to adjust the pH of the reaction mixture to 11-12, and the mixture was heated to 70°C for 0.5 hours. 2 M HCl was added to acidify the pH of the reaction mixture to 2, and the mixture was extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then spin-dried to give the product as a yellow solid (55 mg, 59%).

[0261] LCMS calculation for C 11 H9NO2:187.06; found:188.00[M+1].

[0262] Step 5: Synthesis of 5-cyano-3,7-dihydro-2H-furo[3,2-f]indole (Intermediate 59-5)

[0263] 5-Formyl-3,7-dihydro-2H-furo[3,2-f]indole (55 mg, 0.29 mmol), hydroxylamine hydrochloride (41 mg, 0.59 mmol), and pyridine (0.1 ml) were added to THF (1.0 ml). The reaction was then allowed to react at 80°C for 4 hours. Acetic anhydride (0.22 ml) was then added and allowed to react for 12 hours. Aqueous NaOH (2.0 M) was then added at room temperature to adjust the pH of the reaction solution to 11-12. The mixture was then extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and spun down to dryness to yield a yellow solid product (69 mg).

[0264] Step 6: Synthesis of tert-butyl 4-(5-cyano-2,3-dihydro-7H-furo[3,2-f]indol-7-yl)benzoate (Intermediate 59-6)

[0265] 5-Cyano-3,7-dihydro-2H-furo[3,2-f]indole (250 mg, 1.36 mmol), Cs2CO3 (886 mg, 2.72 mmol), and tert-butyl 4-fluorobenzoate (293 mg, 1.49 mmol) were added to DMF (7 ml). The reaction was then allowed to react at 80°C for 12 hours, then cooled to room temperature. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain the product as a yellow solid (184 mg, 38%).

[0266] MS(ESI)calcd for C 22 H 20N2O3:360.15; found:361.25[M+1].

[0267] 1 H NMR (400MHz, CDCl3) δ8.17(d,J=8.8Hz,2H),7.67(s,1H),7.57(s,1H),7.51(d,J=8 .8Hz,2H),6.90(s,1H),4.65(t,J=8.4Hz,2H),3.34(t,J=8.4Hz,2H),1.63(s,9H).

[0268] Step 7: Synthesis of 4-(5-cyano-2,3-dihydro-7H-furo[3,2-f]indol-7-yl)benzoic acid (Compound 59)

[0269] To TFA (2 ml), tert-butyl 4-(5-cyano-2,3-dihydro-7H-furo[3,2-f]indol-7-yl)benzoate (90 mg, 0.25 mmol) was added. The mixture was allowed to react at room temperature for 2 hours, then concentrated under reduced pressure to dryness, washed with MeOH, and dried to obtain the desired product (45 mg, 59%).

[0270] MS(ESI)calcd for C 18 H 12 N2O3:304.08; found:305.25[M+1].

[0271] 1 H NMR (400MHz, DMSO-D6) δ8.47(s,1H),8.14(d,J=8.4Hz,2H),7.76(d,J=8.4Hz ,2H),7.57(s,1H),7.00(s,1H),4.60(t,J=8.4Hz,2H),3.30(t,J=8.4Hz,2H).

[0272] Example 8 Preparation of Compound 137

[0273] Step 1: Synthesis of 6-bromo-5-amino-2,3-dihydrobenzofuran (Intermediate 137-1)

[0274] 5-Amino-2,3-dihydrobenzofuran (2.0 g, 14.8 mmol) and NBS (2.6 g, 14.8 mmol) were added to acetonitrile (30 ml), and the mixture was stirred at 0°C for 4 hours. After concentration, water was added to the reaction mixture, and dichloromethane was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then passed through a column to obtain a yellowish solid product (600 mg, 19%).

[0275] 1 H NMR (400MHz, CDCl3) δ6.87 (s, 1H), 6.68 (s, 1H), 4.50 (t, J = 8.4Hz, 2H), 3.73 (brs, 2H), 3.10 (t, J = 8.4Hz, 2H).

[0276] Step 2: Synthesis of 6-trimethylsilylene-5-amino-2,3-dihydrobenzofuran (Intermediate 137-2)

[0277] 6-Bromo-5-amino-2,3-dihydrobenzofuran (0.6 g, 2.8 mmol), trimethylsilylene (0.68 g, 7.01 mmol), CuI (534 mg, 2.8 mmol), and Pd(dppf)Cl2 (406 mg, 0.56 mmol) were added to triethylamine (7 ml). The reaction was then allowed to react at 80°C for 48 hours. After concentration, the reaction mixture was treated with water and extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain the product as a white solid (282 mg, 43%).

[0278] 1 H NMR (400MHz, CDCl3) δ6.70(s,1H),6.60(s,1H),4.47(t,J=8.8Hz,2H),3.95(brs,2H),3.12(t,J=8.4Hz,2H),0.25(s,9H).

[0279] Step 3: Synthesis of 3,5-dihydro-2H-furo[2,3-f]indole (Intermediate 137-3)

[0280] 6-Trimethylsilylene-5-amino-2,3-dihydrobenzofuran (282 mg, 1.22 mmol) and CuI (465 mg, 2.44 mmol) were added to DMF (4 ml). The reaction was then allowed to react at 120°C for 1 hour. After concentration, the reaction mixture was treated with water and extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain the product as a white solid (170 mg, 87%).

[0281] 1 H NMR (400MHz, CDCl3) δ7.97(brs,1H),7.19(s,1H),7.13-7.11(m,1H),6.98(s,1H),6.43-6.41(m,1H),4.57(t,J=8.4Hz,2H),3.29(t,J=8.4Hz,2H).

[0282] Step 4: Synthesis of 7-formyl-3,5-dihydro-2H-furo[2,3-f]indole (Intermediate 137-4)

[0283] 3,5-Dihydro-2H-furo[2,3-f]indole (170 mg, 1.07 mmol) and POCl3 (197 mg, 1.28 mmol) were added to DMF (3 ml). The mixture was allowed to react at room temperature for 3 hours. Aqueous NaOH (2.0 M) was then added to adjust the pH of the reaction mixture to 11-12, and the mixture was heated to 70°C for 0.5 hours. 2 M HCl was added to acidify the pH of the reaction mixture to 2, and the mixture was extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then spin-dried to give the product as a red solid (100 mg, 50%).

[0284] 1 H NMR (400MHz, DMSO-D6) δ11.92(brs,1H),9.82(s,1H),8.11(d,J=3.2Hz,1H),7.32(s,2H),4.51(t,J=8.4Hz,2H),3.23(t,J=8.4Hz,2H).

[0285] Step 5: Synthesis of 7-cyano-3,5-dihydro-2H-furo[2,3-f]indole (Intermediate 137-5)

[0286] 7-Formyl-3,5-dihydro-2H-furo[2,3-f]indole (100 mg, 0.53 mmol), hydroxylamine hydrochloride (74 mg, 1.07 mmol), and pyridine (0.2 ml) were added to THF (2.0 ml). The reaction was then allowed to react at 80°C for 4 hours. Acetic anhydride (0.4 ml) was then added and the reaction was allowed to react for 12 hours. Aqueous NaOH (2.0 M) was then added at room temperature to adjust the pH of the reaction solution to 11-12. The mixture was extracted with ethyl acetate, and the organic phase was dried, concentrated under reduced pressure, and spun down to dryness to obtain the product as a yellow solid (98 mg, 99%).

[0287] 1 H NMR (400MHz, DMSO-D6) δ11.95(brs,1H),8.05(d,J=3.2Hz,1H),7.36(s,2H),6.83(s,1H),4.52(t,J=8.4Hz,2H),3.24(t,J=8.4Hz,2H).

[0288] Step 6: Synthesis of tert-butyl 4-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-benzoate (Intermediate 137-6)

[0289] 7-Cyano-3,5-dihydro-2H-furo[2,3-f]indole (300 mg, 1.63 mmol), Cs2CO3 (797 mg, 2.45 mmol), and tert-butyl 4-fluorobenzoate (384 mg, 1.96 mmol) were added to DMF (4 ml). The mixture was allowed to react at 80°C for 12 hours and then cooled to room temperature. The reaction mixture was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain the product as a yellow solid (400 mg, 68%).

[0290] 1 H NMR (400MHz, DMSO-d6) δ8.52(s,1H),8.10(d,J=8.8Hz,2H),7.78(d,J=8.8Hz,2H),7 .56(s,1H),6.99(s,1H),4.59(t,J=8.4Hz,2H),3.27(t,J=8.4Hz,2H),1.58(s,9H).

[0291] Step 7: Synthesis of 4-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-benzoic acid (Intermediate 137-7)

[0292] 4-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-benzoic acid tert-butyl ester (130 mg, 0.36 mmol) was added to TFA (2 ml). The mixture was reacted at room temperature for 2 hours, then concentrated under reduced pressure to dryness, washed with H2O, and dried to obtain the desired product (113 mg, 99%).

[0293] MS(ESI)calcd for C 18 H 12 N2O3:304.08; found:302.85[M-1].

[0294] 1 H NMR (400MHz, DMSO-d6) δ8.53(s,1H),8.15(d,J=8.4Hz,2H),7.78(d,J=8.4Hz,2H ),7.57-7.56(m,1H),6.99(s,1H),4.58(t,J=8.4Hz,2H),3.27(t,J=8.4Hz,2H).

[0295] Step 8: Synthesis of 4-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-benzoic acid THP hydroxyamide (Intermediate 137-8)

[0296] 4-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-benzoic acid (50 mg, 0.16 mmol), HATU (125 mg, 0.33 mmol), DIPEA (64 mg, 0.49 mmol) and NH2OTHP (29 mg, 0.25 mmol) were added to DMF (1 ml). The mixture was allowed to react at room temperature for 12 hours, and then water was added to the reaction mixture. Ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain an off-white solid product (60 mg, 93%).

[0297] MS(ESI)calcd for C 23 H 21 N3O4:403.15; found:404.05[M+1].

[0298] Step 9: Synthesis of 4-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-benzyl amide (Compound 137)

[0299] 4-(7-Cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-benzoic acid THP hydroxyamide (60 mg, 0.15 mmol), THF (0.5 ml), and water (0.5 ml) were added to AcOH (1.5 ml). The reaction was then allowed to proceed at room temperature for 12 hours. The product was filtered, washed with H2O and EtOH, and dried to afford the desired product as an off-white solid (40 mg, 84%).

[0300] MS(ESI)calcd for C 18 H 13 N3O3:319.10; found:320.00[M+1].

[0301] 1 H NMR (400MHz, DMSO-D6) δ11.40(s,1H),9.17(s,1H),8.46(s,1H),7.97(d,J=8.4Hz,2H),7.7 1(d,J=8.4Hz,2H),7.50(s,1H),6.96(s,1H),4.57(t,J=8.4Hz,2H),3.26(t,J=8.4Hz,2H).

[0302] Example 9 Preparation of Compound 22

[0303] Step 1: Synthesis of 6-bromo-2,3-dihydro-1H-inden-5-amine (Intermediate 22-1)

[0304] 2,3-Dihydro-1H-indene-5-amine (2.0 g, 15 mmol) and NBS (2.67 g, 15 mmol) were added to acetonitrile (30 ml), and the mixture was stirred at 0°C for 4 hours. After concentration, the reaction mixture was treated with aqueous NaHCO3 solution, and extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure, and purified by column chromatography to obtain a yellow solid product (1.38 g, 41%).

[0305] Step 2: Synthesis of 6-trimethylsilylene-2,3-dihydro-1H-inden-5-amine (Intermediate 22-2)

[0306] To triethylamine (45 ml), add 6-bromo-2,3-dihydro-1H-inden-5-amine (4.7 g, 20.98 mmol), trimethylsilylene (2.3 g, 23.08 mmol), CuI (400 mg, 2.1 mmol), and Pd(dppf)Cl2 (1.5 g, 2.1 mmol). The reaction mixture was then allowed to react at 80°C for 12 hours. After concentration, the reaction mixture was treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield an off-white solid product (3.0 g, 62%).

[0307] 1 H NMR (400MHz, CDCl3) δ7.14(s,1H),6.59(s,1H),4.10(brs,2H),2.79(t,J=7.6Hz,2H),2.75(t,J=7.6Hz,2H),2.01(pent,J=7.6Hz,2H),0.25(s,9H).

[0308] Step 3: Synthesis of 1,5,6,7-tetrahydrocyclopenta[f]indole (Intermediate 22-3)

[0309] 6-Trimethylsilylene-2,3-dihydro-1H-indene-5-amine (2.3 g, 10.09 mmol) and CuI (0.5 g) were added to DMF (30 ml). The reaction was then allowed to react at 120°C for 2 hours. After concentration, the reaction mixture was treated with water and extracted with dichloromethane. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain a yellow solid product (1.5 g, 73%).

[0310] 1 H NMR (400MHz, CDCl3) δ7.98(brs,1H),7.45(s,1H),7.23(s,1H),7.13-7.12(m,1H),6.47-6.46(m,1H),3.00-2.96(m,4H),2.12(pent,J=7.2Hz,2H).

[0311] Step 4: Synthesis of 3-formyl-1,5,6,7-tetrahydrocyclopenta[f]indole (Intermediate 22-4)

[0312] 1,5,6,7-Tetrahydrocyclopenta[f]indole (700 mg, 4.46 mmol) and POCl3 (820 mg, 5.35 mmol) were added to DMF (10 ml). The mixture was allowed to react at room temperature for 5 hours. A 2.0 M aqueous NaOH solution was then added to adjust the pH to 11-12, and the reaction mixture was heated to 70°C for 0.5 hours. 2 M HCl was added to acidify the pH to 2, and the mixture was extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then spin-dried to afford the product as a red solid (700 mg, 85%).

[0313] MS(ESI)calcd for C 12 H 11 NO:185.08; found:185.85[M+1].

[0314] 1 H NMR (400MHz, CDCl3) δ10.02(s,1H),8.76(brs,1H),8.14(s,1H),7.77(d,J=3.2Hz,1H),7.26(s,1H),3.03-2.97(m,4H),2.13(pent,J=7.2Hz,2H).

[0315] Step 5: Synthesis of 3-cyano-1,5,6,7-tetrahydrocyclopenta[f]indole (Intermediate 22-5)

[0316] 3-Formyl-1,5,6,7-tetrahydrocyclopenta[f]indole (700 mg, 3.78 mmol), hydroxylamine hydrochloride (525 mg, 7.56 mmol), and pyridine (1.5 ml) were added to THF (10.0 ml). The reaction was then allowed to react at 80°C for 4 hours. Acetic anhydride (2.0 ml) was then added and the reaction was allowed to react for 12 hours. Aqueous NaOH (2.0 M) was then added at room temperature to adjust the pH of the reaction solution to 11-12. The reaction solution was extracted with ethyl acetate, and the organic phase was dried, concentrated under reduced pressure, and then spin-dried to yield the product as a yellow solid (700 mg, 99%).

[0317] 1 H NMR (400MHz, DMSO-D6) δ11.99(brs,1H),8.10(s,1H),7.41(s,1H),7.35(s,1H),2.93(t,J=7.2Hz,4H),2.05(pent,J=7.2Hz,2H).

[0318] Step 6: Synthesis of ethyl 4-(3-cyano-6,7-dihydrocyclopenta[f]indol-1(5H)-yl)-2-(methoxymethyleneoxy)benzoate (Intermediate 22-6)

[0319] 3-Cyano-1,5,6,7-tetrahydrocyclopenta[f]indole (700 mg, 3.84 mmol), Cs2CO3 (3.1 g, 9.6 mmol), and ethyl 4-fluoro-2-(methoxymethyleneoxy)benzoate (1.3 g, 5.77 mmol) were added to DMF (10 ml). The reaction was then allowed to react at 85°C for 12 hours, then cooled to room temperature. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield an off-white solid (600 mg, 40%).

[0320] MS(ESI)calcd for C 23 H 22 N2O4:390.16; found:391.00[M+1].

[0321] 1 H NMR (400MHz, DMSO-D6) δ8.54(s,1H),7.87(d,J=8.4Hz,1H),7.55(s,1H),7.54(s,1H),7.46(d,J=2.0Hz,1H),7.37(dd,J=8.4and 2.0Hz,1H),5.38(s,2H),4.32(q,J=6.8Hz,2H),3.44(s,3H),3.00-2.93(m,4H),2.07(pent,J=7.6Hz,2H),1.32(t,J=6.8Hz,3H).

[0322] Step 7: Synthesis of ethyl 4-(3-cyano-6,7-dihydrocyclopenta[f]indol-1(5H)-yl)-2-hydroxybenzoate (Intermediate 22-7)

[0323] To THF (1.5 ml) was added ethyl 4-(3-cyano-6,7-dihydrocyclopenta[f]indol-1(5H)-yl)-2-(methoxymethyleneoxy)benzoate (300 mg, 0.77 mmol), EtOH (1 ml), and HCl (2.0 M, 1.5 ml). The mixture was then reacted at 70°C for 1 hour and cooled to room temperature. The product was filtered, washed with EtOH and H2O, and dried to afford an off-white solid (120 mg, 33%).

[0324] MS(ESI)calcd for C 21 H 18N2O3:346.13; found:346.85[M+1].

[0325] 1 H NMR (400MHz, DMSO-D6) δ10.85(s,1H),8.53(s,1H),7.97(d,J=8.8Hz,1H),7.54(s,1H),7.53(s,1H),7.25 -7.22(m,2H),4.40(q,J=7.2Hz,2H),2.98-2.93(m,4H),2.06(pent,J=7.2Hz,2H),1.36(t,J=7.2Hz,3H).

[0326] Step 8: Synthesis of 4-(3-cyano-6,7-dihydrocyclopenta[f]indol-1(5H)-yl)-2-hydroxybenzoic acid (Compound 22)

[0327] To THF (1 ml), ethyl 4-(3-cyano-6,7-dihydrocyclopenta[f]indol-1(5H)-yl)-2-hydroxybenzoate (100 mg, 0.27 mmol), H₂O (0.5 ml), and LiOH (140 mg) were added. The mixture was allowed to react at room temperature for 72 hours. HCl (2.0 M) was then added to acidify the pH of the reaction solution to 2. Ethyl acetate was then added for extraction. The organic phase was washed with H₂O, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to afford an off-white solid product (88 mg, 97%).

[0328] MS(ESI)calcd for C 19 H 14 N2O3:318.10; found:316.90[M-1].

[0329] 1 H NMR (400MHz, DMSO-D6) δ8.52(s,1H),7.97(d,J=8.8Hz,1H),7.54(s,1H),7.53(s,1H),7.21-7.18(m,2H),2.98-2.93(m,4H),2.09-2.02(m,2H).

[0330] Example 10 Preparation of Compound 34

[0331] Step 1: Synthesis of 3-bromo-5,7-dihydro-1H-furo[3,4-f]indole (Intermediate 34-1)

[0332] 5,7-Dihydro-1H-furo[3,4-f]indole (1.0 g, 6.37 mmol) and NBS (906 mg, 5.09 mmol) were added to dichloromethane (14 ml). The mixture was allowed to react at room temperature for 0.5 hours. Water was then added to the reaction mixture, and ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain an off-white solid product (321 mg, 21%).

[0333] MS(ESI)calcd for C 10 H8BrNO:236.98; found:235.90,237.90[M-1].

[0334] Step 2: Synthesis of ethyl 4-(3-bromo-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyleneoxy)benzoate (Intermediate 34-2)

[0335] To DMF (3 ml), add 3-bromo-5,7-dihydro-1H-furo[3,4-f]indole (170 mg, 0.72 mmol), Cs2CO3 (584 mg, 1.79 mmol), and ethyl 4-fluoro-2-(methoxymethyleneoxy)benzoate (245 mg, 1.08 mmol). The reaction was then allowed to react at 80°C for 12 hours, then cooled to room temperature. The reaction was then treated with water and extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to yield an off-white solid (175 mg, 55%).

[0336] MS(ESI)calcd for C 21 H 20 BrNO5:445.05; found:446.00,448.00[M+1].

[0337] 1 H NMR (400MHz, CDCl3) δ7.97(d,J=8.4Hz,1H),7.45(s,1H),7.42(s,1H),7.39(s,1H),7.31(d,J=2.0Hz,1H),7.17(dd,J=8.4and 2.0Hz,1H),5.31(s,2H),5.21(s,2H),5.18(s,2H),4.40(q,J=7.2Hz,1H),3.54(s,3H),1.41(t,J=7.2Hz,3H).

[0338] Step 3: Synthesis of ethyl 4-(3-bromo-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (Intermediate 34-3)

[0339] To THF (3 ml), add ethyl 4-(3-bromo-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-(methoxymethyleneoxy)benzoate (170 mg, 0.38 mmol), EtOH (2 ml), and HCl (2.0 M, 3 ml). The mixture was reacted at 60°C for 4 hours, then cooled to room temperature. The product was filtered, washed with EtOH and H2O, and dried to afford an off-white solid (150 mg).

[0340] MS(ESI)calcd for C 19 H 16 BrNO4:401.03; found:399.90,401.90[M-1].

[0341] Step 4: Synthesis of 4-(3-bromo-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoic acid (Compound 34)

[0342] To THF (2.3 ml) was added ethyl 4-(3-bromo-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-hydroxybenzoate (100 mg, 0.25 mmol), H₂O (1.0 ml), and LiOH (124 mg). The mixture was allowed to react at room temperature for 72 hours. HCl (2.0 M) was then added to acidify the reaction solution to pH 2. Ethyl acetate was then added for extraction. The organic phase was washed with H₂O, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to afford a gray solid product (23 mg, 25%).

[0343] MS(ESI)calcd for C 17 H 12 BrNO4:372.99; found:371.85,373.85[M-1].

[0344] 1 H NMR (400MHz, DMSO-D6) δ8.00 (s, 1H), 7.94 (d, J = 8.4Hz, 1H), 7.65 (s, 1H), 7.42 (s, 1H), 7.22-7.17 (m, 2H), 5.07 (s, 4H).

[0345] Example 11 Preparation of Compound 35

[0346] Step 1: Synthesis of 5-(3-formyl-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-cyanopyridine (Intermediate 35-1)

[0347] 3-Formyl-5,7-dihydro-1H-furo[3,4-f]indole (500 mg, 2.67 mmol), 40% KF / Al2O3 (500 mg), 18-crown-6 (70 mg), and 5-fluoro-2-cyanopyridine (650 mg, 5.34 mmol) were added to DMSO (10 ml). The mixture was then reacted in a sealed tube at 120°C for 12 hours and cooled to room temperature. The reaction mixture was then treated with water (30 ml) and ethyl acetate (10 ml), filtered, washed with EtOH, and dried to yield an off-white solid (550 mg, 71%).

[0348] MS(ESI)calcd for C 17 H 11 N3O2:289.09; found:287.95[M-1].

[0349] Step 2: Synthesis of 1-(6-(tetrazol-1H-5-yl)pyridin-3-yl)-3-formyl-5,7-dihydro-1H-furo[3,4-f]indole (Intermediate 35-2)

[0350] 5-(3-Formyl-5,7-dihydro-1H-furo[3,4-f]indol-1-yl)-2-cyanopyridine (200 mg, 0.69 mmol), NaN3 (157 mg), and triethylamine hydrochloride (190 mg) were added to NMP (2.5 ml). The reaction was then carried out in a sealed tube at 120°C for 12 hours, followed by cooling to room temperature. Water was then added to adjust the pH to 3.0. The product was filtered, washed with MeOH, and dried to afford a brown solid (100 mg, 43%).

[0351] MS(ESI)calcd for C 17 H 12 N6O2:332.10; found:330.90[M-1].

[0352] 1 H NMR (400MHz, DMSO-D6) δ10.06(s,1H),9.16(brs,1H),8.77(s,1H),8.47(s,2H),8.12(s,1H),7.62(s,1H),5.11(s,2H),5.07(s,2H).

[0353] Step 3: Synthesis of 1-(6-(tetrazol-1H-5-yl)pyridin-3-yl)-3-cyano-5,7-dihydro-1H-furo[3,4-f]indole (Compound 35)

[0354] 1-(6-(tetrazol-1H-5-yl)pyridin-3-yl)-3-formyl-5,7-dihydro-1H-furo[3,4-f]indole (30 mg, 0.09 mmol), hydroxylamine hydrochloride (9 mg), and sodium formate (18 mg) were added to HCO₂H₂ (1.0 ml). The reaction was then incubated at 105°C for 2 hours and cooled to room temperature. Water was then added and filtered to obtain a brown solid product, which was then recrystallized from DMF and dried to yield a light brown solid product (11 mg, 33%).

[0355] MS(ESI)calcd for C 17 H 11 N7O:329.10; found:327.90[M-1].

[0356] 1 H NMR (400MHz, DMSO-D6) δ9.13(s,1H),8.76(s,1H),8.44(s,2H),7.70-7.67(m,2H),5.10(s,2H),5.06(s,2H).

[0357] Example 12 Preparation of Compound 138

[0358] Step 1: Synthesis of 5-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-pyridine-2-carboxylic acid methyl ester (Intermediate 138-1)

[0359] 7-Cyano-3,5-dihydro-2H-furo[2,3-f]indole (200 mg, 1.09 mmol), Cs2CO3 (889 mg, 2.73 mmol), and 5-fluoro-pyridine-2-carboxylic acid methyl ester (253 mg, 1.63 mmol) were added to DMF (2 ml). The reaction was then allowed to react at 80°C for 12 hours, then cooled to room temperature. The reaction mixture was then treated with water, filtered, washed with H2O, and dried to yield the product as a yellow solid (259 mg, 78%).

[0360] MS(ESI)calcd for C 18 H 13 N3O3:319.10; found:320.25[M+1].

[0361] 1H NMR(400MHz,DMSO-d6)δ9.03(d,J=2.4Hz,1H),8.62(s,1H),8.34(dd,J=8.8and2.4Hz,1H),8.26(d, J=8.8Hz,1H),7.62(s,1H),7.01(s,1H),4.60(t,J=8.4Hz,2H),3.94(s,3H),3.27(t,J=8.4Hz,2H).

[0362] Step 2: Synthesis of 5-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-pyridine-2-carboxylic acid (Intermediate 138-2)

[0363] To THF (1 ml), methyl 5-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-pyridine-2-carboxylate (100 mg, 0.13 mmol) and LiOH (2.0 M, 1.9 ml) were added. The mixture was allowed to react at room temperature for 72 hours, and then the pH of the reaction solution was adjusted to 2 by adding HCl (2.0 M). The off-white solid product was filtered, washed with H2O and EtOAc, and dried to obtain the desired product (80 mg, 85%).

[0364] MS(ESI)calcd for C 17 H 11 N3O3:305.08; found:306.25[M+1].

[0365] 1 H NMR(400MHz,DMSO-d6)δ9.06(d,J=2.4Hz,1H),8.89(s,1H),8.43(dd,J=8.8 and 2.4Hz,1H),8.41(s,1H),7.93(d,J=8.8Hz,1H),6.95(s,1H),4.59(t,J=8.4Hz,2H),3.31(t,J=8.4Hz,2H).

[0366] Step 3: Synthesis of 5-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)pyridine-2-carboxylic acid THP hydroxyamide (Intermediate 138-3)

[0367] 5-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-pyridine-2-carboxylic acid (40 mg, 0.13 mmol), HATU (100 mg, 0.26 mmol), DIPEA (51 mg, 0.39 mmol) and NH2OTHP (23 mg, 0.20 mmol) were added to DMF (1 ml). The mixture was allowed to react at room temperature for 12 hours, and then water was added to the reaction mixture. Ethyl acetate was added for extraction. The organic phase was dried, concentrated under reduced pressure, and then filtered through a column to obtain a yellow solid product (35 mg, 62%).

[0368] MS(ESI)calcd for C 22 H 20 N4O4:404.15; found:405.25[M+1].

[0369] Step 4: Synthesis of 5-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)pyridine-2-carboxylic acid hydroxyamide (Compound 138)

[0370] To AcOH (0.9 ml) were added 5-(7-cyano-2,3-dihydro-5H-furo[2,3-f]indol-5-yl)-pyridine-2-carboxylic acid THP hydroxyamide (34 mg, 0.08 mmol), THF (0.3 ml), and water (0.3 ml). The reaction was allowed to react at room temperature for 12 hours. The mixture was concentrated under reduced pressure and treated with water. The reaction mixture was filtered, washed with H2O and EtOAc, and dried to afford the desired product as an off-white solid (18 mg, 70%).

[0371] MS(ESI)calcd for C 17 H 12 N4O3:320.09; found:321.25[M+1].

[0372] 1 H NMR(400MHz,DMSO-D6)δ9.30(s,1H),8.95-8.87(m,2H),8.39-8.32(m,2H),7. 94(d,J=8.4Hz,1H),6.97(s,1H),4.61(t,J=8.0Hz,2H),3.31(t,J=8.0Hz,2H).

[0373] Referring to the preparation methods of Examples 1-12, Compounds 1-138 were prepared. The examples to which their preparation methods refer, as well as their structural formulas and characterization data are shown in Table 1.

[0374] Table 1 Structural formula, characterization data and preparation methods of Compounds 1 to 138

[0375] Example 13 Inhibition of xanthine oxidase activity by the compound

[0376] Weigh 2-3 mg of the test compound, including the positive control febuxostat, and dissolve it in DMSO to a 10 mM stock solution. Gradual dilutions were made into 8 concentration gradients (500 uM, 50 uM, 5 uM, 500 nM, 250 nM, 50 nM, 5 nM, 0.5 nM) containing the same concentration of DMSO (5%).

[0377] The xanthine oxidase activity assay kit (MAK078-1KT) was purchased from the official website of Merck. Mouse liver tissue (500 μl / 30 mg) was homogenized with the kit's assay buffer to obtain a tissue homogenate containing mouse xanthine oxidase. The homogenate was centrifuged at 10,000 rpm for 10 minutes at 4°C. The supernatant was transferred to a new centrifuge tube and placed on ice until ready to use.

[0378] Add 50ul of tissue homogenate to a 96-well plate, add 2ul of the test compound at the corresponding concentration, and then add 48ul of the mixture containing the other components of the kit, with a total volume of 100ul / well. Incubate at 25°C for 3 minutes, excite at 535nm, and read the excited fluorescence intensity at 587nm (the more superoxide radicals generated in the reaction system due to the oxidation of hypoxanthine and xanthine by xanthine oxidase, the more resorufin will react with 10-acetyl-3,7-dihydroxyphenoxazine in the system, and the higher the excited fluorescence intensity, indicating higher xanthine oxidase activity). At 25°C, read the results kinetically every 3 minutes for 15 minutes. The wells without inhibitor are considered 100% xanthine oxidase activity, and the wells without enzyme are considered zero activity (background). After reading the plate, perform QC to confirm that the 12-minute point is in the linear range. Analyze the inhibition efficiency at the 12-minute point to obtain the IC value of the test compound. 50 .

[0379] The test results are shown in Table 2: The dihydrofuranoindole compounds or their derivatives of the present invention have a strong inhibitory effect on the activity of xanthine oxidase, and the inhibitory activity of some compounds is better than that of the positive drug febuxostat.

[0380] Table 2. Inhibition results of compounds on xanthine oxidase activity

[0381] Example 14 Inhibition of uric acid transporter by the compound

[0382] As in Example 13, concentration gradients of the test compound and the positive control (lesinurad) were prepared.

[0383] All cell culture media were purchased from Invitrogen, and plastics from Corning. Because renal tubular epithelial cells express Urat1 and Glut9, they can be used to assay urate transporter activity. Mouse renal tubular epithelial cells were seeded onto 0.4 μm pore size cell culture transwell membranes and cultured until the cells completely confluently filled the transwell, forming a monolayer. Prior to testing the test compound, the transwell chamber was replaced with DMEM basal medium containing the test compound at the specified concentration and 4.5 mg / dL uric acid. The bottom layer of the multiwell plate was replaced with DMEM basal medium without uric acid. After incubation at 37°C for 60 minutes, 100 μl of medium was removed from the bottom layer of the multiwell plate, and uric acid concentrations were read at 290 nm using a microplate reader. Wells without uric acid served as blank controls, and wells without compound were considered 100% transport. The uric acid concentrations in the wells corresponding to the test compound were compared with those in the wells with 100% transport to determine the inhibition efficiency.

[0384] The results showed that lesinurad at a concentration of 1000 nM had an inhibition rate of 23.63% on uric acid transporter activity, while compound 12 at a concentration of 250 nM had an inhibition rate of 64.27%. This indicates that the compounds of the present invention have strong inhibitory activity against uric acid transporter activity, with their inhibitory activity at a concentration of 250 nM being higher than that of lesinurad at a concentration of 1000 nM.

[0385] Example 15 Inhibition of uric acid transporter by the compound

[0386] In this example, a third party (Beijing Kanglong Chemical Co., Ltd.) was commissioned to use HEK-293 cells (HEK293-hURAT1) that stably overexpress the human urate transporter (protein name URAT1, gene name SLC22A12) as a cell model for studying urate transport to determine the inhibitory activity of compounds against the human urate transporter. Concentration gradients of the test compound and the positive control (lesinurad) were prepared as in Example 13. All cell culture media were purchased from Invitrogen, and plastics were purchased from Corning. C14-labeled uric acid was obtained from VWR, USA. The specific procedures were as follows:

[0387] Cells were pre-plated in 96-well plates. The next day, the culture medium was replaced with culture medium pre-mixed with C14-labeled uric acid and varying concentrations of a positive control or other test compound. After a 5-minute incubation, the culture medium was removed, the cells were lysed with 0.1N NaOH, and the supernatant was read using a Perkin Elmer liquid scintillation counter (Model MicroBeta2). The reading for wells containing C14-labeled uric acid but no compound was considered 100% uric acid transport, while the reading for wells without C14-labeled uric acid was considered background. The inhibitory efficacy of the positive control compound or test compound at varying concentrations on the uric acid transporter was calculated to obtain the IC50.

[0388] The test results are shown in Table 3: The activity of compound 12 in the present invention in inhibiting uric acid transporter is significantly higher than that of the positive control drug lesinurad. It can be seen that the compound of the present invention has good inhibitory activity on uric acid transporter.

[0389] Table 3 Inhibition results of compounds on uric acid transporter

[0390] Example 16: Pharmacological Efficacy Test of Compounds in Lowering Uric Acid in the Body

[0391] In this example, Balb / c wild-type adult male mice aged 8-12 weeks provided by Weitonglihua Company were divided into a control group (vehicle) and a treatment group (6 mice per group) to test the efficacy of the compound in reducing uric acid in the body. The specific experimental method is as follows:

[0392] The control group was given 0.5 ml of a 1.2% 2-BP-β-CD (cyclodextrin) solution prepared in water, and the drug-treated group was given 0.5 ml of a solution prepared in water containing 1.2% 2-BP-β-CD (cyclodextrin) and 1.6 mg / ml of the test compound. 7 hours, 15 hours, or 23 hours after administration, 0.5 ml of a mixed solution containing 60 mg / ml potassium oxonate (an inhibitor of uricase) and 6.67 mg / ml hypoxanthine (a substrate of xanthine oxidase) prepared in 0.5% methylcellulose aqueous solution was orally administered to induce hyperuricemia. One hour later, 100 μl of peripheral blood was collected from the inner orbit, and the serum uric acid concentration was determined using the conventional phosphotungstic acid method.

[0393] The results are shown in FIG1 . 8 hours after administration, compound 4, compound 12, and compound 137-7 can effectively reduce the blood uric acid concentration to about half compared with the control group.

[0394] The technical features of the above-described embodiments can be combined arbitrarily. To make the description concise, not all possible combinations of the technical features in the following embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0395] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. A dihydrofuranoindole compound having the structure shown in Formula I, or a derivative thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuterated compound thereof, or a tritiated compound thereof, in, X is selected from: O, S, C(R 1 )2、NR 2 ; Z and W are independently selected from: CR 3 , N; m and n are independently selected from: 0, 1, 2, 3, and m+n is 2, 3 or 4; Q is selected from: hydrogen, one or more R 4 Substituted or unsubstituted C1-C6 alkyl, one or more R 4 Substituted or unsubstituted C1-C6 alkoxy, one or more R 4 Substituted or unsubstituted C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, one or more R 5 Substituted or unsubstituted C3-C8 cycloalkyl, one or more R 5 a substituted or unsubstituted 3-8 membered heterocyclic group, one or more R 6 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 6 substituted or unsubstituted 5-10 membered heteroaryl, L is selected from: hydrogen, one or more R 4 Substituted or unsubstituted C1-C6 alkyl, one or more R 4 Substituted or unsubstituted C1-C6 alkoxy, one or more R 4 Substituted or unsubstituted C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, one or more R 5 Substituted or unsubstituted C3-C8 cycloalkyl, one or more R 5 a substituted or unsubstituted 3-8 membered heterocyclic group, one or more R 6 Substituted or unsubstituted C6-C 10 Aryl, 1 or more R 6 substituted or unsubstituted 5-10 membered heteroaryl, X 1 、X 2 are independently selected from: O, S, C(R 1 )2、NR 2 ; Z 1 , Z 2 and Z 3 Independently selected from: CR 3 , N; Each R 1 Each is independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and halogen; Each R 2 are independently selected from: hydrogen, C1-C6 alkyl; Each R 3 Each is independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and halogen; Each R 4 Each of the following is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; Each R 5 are independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl; Each R 6 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, -C(=O)R, nitro, hydroxy, mercapto, amino, R 5 Substituted or unsubstituted C6-C 10 Aryl, R 5 substituted or unsubstituted 5-10 membered heteroaryl; Each R is independently selected from the group consisting of hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino.

2. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 1, characterized in that: The dihydrofuranoindole compound or its derivative has a structure as shown in Formula II:

3. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 1, characterized in that: The dihydrofuroindole compound or its derivative has a structure as shown in Formula III-1, Formula III-2, Formula III-3, Formula III-4, Formula III-5, Formula III-6, Formula III-7, Formula III-8, Formula III-9, Formula III-10, Formula III-11, Formula III-12, Formula III-13, Formula III-14, Formula III-15, Formula III-16, Formula III-17 or Formula III-18:

4. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 3, characterized in that: In formula III-1, each R 1 are independently selected from: hydrogen, C1-C3 alkyl, halogen; Each R in Formula III-8, Formula III-9, and Formula III-10 2 are independently selected from: hydrogen, C1-C3 alkyl; Preferably, each R in formula III-1 1 Each is independently selected from: hydrogen, methyl, ethyl, fluorine, chlorine, bromine; Preferably, each R of formula III-8, formula III-9, and formula III-10 2 are independently selected from the group consisting of: hydrogen, methyl, and ethyl.

5. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: X 1 、X 2 are independently selected from: O, S, C(R 1 )2、NR 2 ; Z 1 , Z 2 and Z 3 Independently selected from: CR 3 , N; Each R 1 Each is independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluorine, chlorine, and bromine; Each R 2 are independently selected from: hydrogen, C1-C3 alkyl; Each R 3 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen; Preferably, X 1 Selected from: O, S, X 2 NR 2 , R 2 Selected from: hydrogen, methyl, ethyl, propyl; Preferably, Z 1 , Z 2 and Z 3 One or two of them are N, and the others are CR 3 , R 3 Selected from: hydrogen, methyl, ethyl, propyl.

6. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: Each R 4 Each of the following is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclyl; Preferably, each R 4 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxanyl, tetrahydropyrrolyl, and tetrahydrothiophenyl.

7. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated substance, or its tritiated substance according to any one of claims 1 to 3, characterized in that: Each R 5 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl; Preferably, each R 5 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, and hydroxyl.

8. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: Each R 6 are independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, -C(=O)R, nitro, hydroxy, mercapto, amino, R 5 Substituted or unsubstituted phenyl, R 5 Substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 5-6 membered heteroaryl; Each R is independently selected from the group consisting of hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkylamino; Preferably, each R 6 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyacyl, ethoxyacyl, carbamoyl, nitro, hydroxyl, mercapto, amino, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, tetrazolyl, furyl, thienyl, pyrrolyl, and imidazolyl.

9. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: Q is selected from: hydrogen, one or more R 4 Substituted or unsubstituted C1-C3 alkyl, one or more R 4 Substituted or unsubstituted C1-C3 alkoxy, one or more R 4 Substituted or unsubstituted C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, one or more R 5 Substituted or unsubstituted C3-C6 cycloalkyl, one or more R 5 a substituted or unsubstituted 3-6 membered heterocyclic group, one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6 substituted or unsubstituted 5-6 membered heteroaryl, X 1 、X 2 are independently selected from: O, S, C(R 1 )2、NR 2 ; Z 1 , Z 2 and Z 3 Independently selected from: CR 3 , N; Each R 1 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen; Each R 2 are independently selected from: hydrogen, C1-C3 alkyl; Each R 3 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen; Preferably, each R 4 Each of the following is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclyl; Preferably, each R 5 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl; Preferably, each R 6 are independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, C(=O)R, nitro, hydroxy, mercapto, amino, R 5 Substituted or unsubstituted phenyl, R 5 Substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 5-6 membered heteroaryl; Each R is independently selected from the group consisting of hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkylamino.

10. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated substance, or its tritiated substance according to claim 9, characterized in that: Q is selected from the group consisting of hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxacyclohexanyl, tetrahydropyrrolyl, tetrahydrothienyl, halogen-substituted tetrahydropyrrolyl, hydroxy-substituted tetrahydropyrrolyl, azetidinyl, halogen-substituted azetidinyl, hydroxy-substituted azetidinyl, one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6 Substituted or unsubstituted pyridyl, one or more R 6 Substituted or unsubstituted pyrazinyl, one or more R 6 Substituted or unsubstituted pyridazinyl, one or more R 6 substituted or unsubstituted pyrimidinyl, Preferably, each R 6 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyacyl, ethoxyacyl, carbamoyl, nitro, hydroxyl, mercapto, amino, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, tetrazolyl, furyl, thienyl, pyrrolyl, and imidazolyl.

11. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 10, characterized in that: Q is selected from: chlorine, bromine, aldehyde, cyano, difluoromethyl, Preferably, Q is selected from the group consisting of chlorine, bromine, aldehyde, and cyano, more preferably cyano.

12. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: L is selected from: hydrogen, one or more R 4 Substituted or unsubstituted C1-C3 alkyl, one or more R 4 Substituted or unsubstituted C1-C3 alkoxy, one or more R 4 Substituted or unsubstituted C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, one or more R 5 Substituted or unsubstituted C3-C6 cycloalkyl, one or more R 5 a substituted or unsubstituted 3-6 membered heterocyclic group, one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6 substituted or unsubstituted 5-6 membered heteroaryl, X 1 、X 2 are independently selected from: O, S, C(R 1 )2、NR 2 ; Z 1 , Z 2 and Z 3 Independently selected from: CR 3 , N; Each R 1 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen; Each R 2 are independently selected from: hydrogen, C1-C3 alkyl; Each R 3 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and halogen; Preferably, each R 4 Each of the following is independently selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, hydroxyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclyl; Preferably, each R 5 are independently selected from the group consisting of: hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, aldehyde, carboxyl, nitro, and hydroxyl; Preferably, each R 6 are independently selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-substituted C1-C3 alkoxy, C1-C3 alkylthio, halogen, cyano, C(=O)R, nitro, hydroxy, mercapto, amino, R 5 Substituted or unsubstituted phenyl, R 5 Substituted or unsubstituted naphthyl, R 5 substituted or unsubstituted 5-6 membered heteroaryl; Each R is independently selected from the group consisting of hydrogen, hydroxyl, hydroxyamino, amino, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkylamino.

13. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 12, characterized in that: L is selected from the group consisting of hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, nitro, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, oxane, tetrahydropyrrolyl, tetrahydrothienyl, halogen-substituted tetrahydropyrrolyl, hydroxy-substituted tetrahydropyrrolyl, azetidinyl, halogen-substituted azetidinyl, hydroxy-substituted azetidinyl, one or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6 Substituted or unsubstituted pyridyl, one or more R 6 Substituted or unsubstituted pyrazinyl, one or more R 6 Substituted or unsubstituted pyridazinyl, one or more R 6 substituted or unsubstituted pyrimidinyl, Preferably, each R 6 Each of the following groups is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -C(=O)NHOH, formyl, acetyl, methoxyacyl, ethoxyacyl, carbamoyl, nitro, hydroxyl, mercapto, amino, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, methoxy-substituted methoxy, methoxy-substituted ethoxy, methoxy-substituted propoxy, phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, tetrazolyl, furyl, thienyl, pyrrolyl, and imidazolyl.

14. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 13, characterized in that: L is selected from: Preferably, L is selected from: More preferably, L is or 15. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: Q is selected from: halogen, aldehyde, cyano, oxygen-containing 3-5 membered heterocyclic group; L is selected from: 1 or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridyl, one or more R 6 Substituted or unsubstituted pyrazinyl, one or more R 6 substituted or unsubstituted pyrimidinyl, Among them, each R 6 Each is independently selected from the group consisting of hydrogen, methyl, ethyl, halogen, carboxyl, hydroxyl, tetrazolyl, and C(=O)NHOH.

16. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 15, characterized in that: Q is selected from: chlorine, bromine, aldehyde, cyano, L is selected from:

17. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated substance, or its tritiated substance according to any one of claims 1 to 3, characterized in that: Q is halogen, preferably chlorine or bromine; L is selected from: 1 or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6 substituted or unsubstituted 5-6 membered heteroaryl, Each R 6 Each is independently selected from: hydrogen, hydroxyl, carboxyl, tetrazolyl; Preferably, L is selected from: R 6 Substituted or unsubstituted phenyl, R 6 substituted or unsubstituted pyridyl; Preferably, L is selected from: More preferably, L is selected from: More preferably, L is or 18. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: Q is a cyano group; L is selected from: 1 or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6 substituted or unsubstituted 5-6 membered heteroaryl, Each R 6 Each is independently selected from the group consisting of hydrogen, methyl, ethyl, hydroxy, carboxyl, halogen, tetrazolyl, and C(=O)NHOH; Preferably, each R 6 Each is independently selected from the group consisting of hydrogen, hydroxy, carboxyl, tetrazolyl, and C(=O)NHOH.

19. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 18, characterized in that: L is selected from: 1 or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridyl, one or more R 6 Substituted or unsubstituted pyrazinyl, one or more R 6 substituted or unsubstituted pyrimidinyl, More preferably, L is selected from: 1 or more R 6 Substituted or unsubstituted pyridyl, one or more R 6 substituted or unsubstituted pyrazinyl, 20. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 18, characterized in that: L is selected from: Preferably, L is selected from:

21. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to any one of claims 1 to 3, characterized in that: Q is an aldehyde group; L is selected from: 1 or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted naphthyl, one or more R 6 a substituted or unsubstituted 5-6 membered heteroaryl group; Each R 6 Each is independently selected from: hydrogen, hydroxyl, carboxyl, tetrazolyl; Preferably, L is selected from: 1 or more R 6 Substituted or unsubstituted phenyl, one or more R 6 Substituted or unsubstituted pyridyl, one or more R 6 a substituted or unsubstituted pyrimidinyl group; Preferably, L is selected from: More preferably, L is selected from:

22. The dihydrofuroindole compound or its derivative, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound according to claim 1, characterized in that: The dihydrofuranoindole compound or its derivative is selected from the following compounds: Alternatively, the dihydrofuranoindole compound or its derivative is selected from the following compounds: Preferably, the dihydrofuranoindole compound or its derivative is selected from the following compounds: Preferably, the dihydrofuranoindole compound or its derivative is selected from the following compounds: Preferably, the dihydrofuranoindole compound or its derivative is selected from the following compounds:

23. Use of the dihydrofuroindole compound or its derivative, stereoisomer, pharmaceutically acceptable salt, solvate, prodrug, deuteride, or tritium according to any one of claims 1 to 22 in the preparation of an XOR inhibitor and / or a URAT1 inhibitor.

24. Use of the dihydrofuroindole compound or its derivative, or stereoisomer, or pharmaceutically acceptable salt, or solvate, or prodrug molecule, or deuteride, or tritium according to any one of claims 1 to 22 in the preparation of a uric acid-lowering drug.

25. Use of the dihydrofuroindole compound or its derivative, or stereoisomer, or pharmaceutically acceptable salt, or solvate, or prodrug molecule, or deuteride, or tritium according to any one of claims 1 to 22 in the preparation of a medicament for preventing and / or treating gout or hyperuricemia.

26. A XOR / URAT1 dual inhibitor, characterized in that The active ingredient contains the dihydrofuranoindole compound or its derivative according to any one of claims 1 to 22, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritium.

27. A uric acid-lowering drug, characterized in that: The active ingredient is prepared from an active ingredient and a pharmaceutically acceptable carrier or excipient, wherein the active ingredient includes the dihydrofuranoindole compound or its derivative according to any one of claims 1 to 22, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuteride, or its tritide.

28. A method for preventing and / or treating gout or hyperuricemia, characterized in that: Said include: Administering a safe and effective amount of any one of the dihydrofuranoindole compounds described in 1-22, or its derivatives, or stereoisomers, or pharmaceutically acceptable salts, or solvates, or prodrug molecules, or deuterated compounds, or tritiated compounds thereof, to a patient suffering from gout or hyperuricemia; and / or, Administer a safe and effective amount of the uric acid-lowering drug according to claim 27 to a patient with gout or hyperuricemia.

Images